A cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an intracellular second messenger substance, is decomposed and inactivated by phosphodiesterase (PDE 1 to PDE 11). The PDE 7 selectively decomposes cAMP, and is characterized as an enzyme not decomposed by rolipram. Rolipram is a selective inhibitor of PDE 4 which decomposes cAMP.
It is suggested that PDE 7 plays an important role for activating T cells (Beavo, et al., Science, 283, 848 (1999)), and well known that activating of T-cell is concerned with the exacerbation of allergic disease, inflammatory disease or immunologic disease. These diseases are for example, bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia, Crohn's disease, rejection for organ transplantation, graft versus host disease (GVH disease), and restenosis after angioplasty. [J. Allergy Clin. Immunol., 2000 November; 106 (5 Suppl.): S221-6; Am. J. Respir. Crit. Care Med., 1996 February; 153(2): 629-32; Am. J. Respir. Crit. Care Med., 1999 November; 160 (5 Pt 2): S33-7; Clin. Exp. Allergy, 2000 February; 30(2): 242-54; Hosp. Med., 1998 July; 59(7): 530-3; Int. Arch. Allergy Immunol., 1998 March; 115(3): 179-90; J. Immunol., 1991 February 15; 146(4): 1169-74; Osteoarthritis Cartilage, 1999 July; 7(4): 401-2; Rheum. Dis. Clin. North Am., 2001 May; 27(2): 317-34; J. Autoimmun., 2001 May; 16(3): 187-92; Curr. Rheumatol. Rep., 2000 February; 2(1): 24-31; Trends Immunol., 2001 January; 22 (1): 21-6; Curr. Opin. Immunol., 2000 August; 12(4): 403-8; Diabetes Care, 2001 September; 24(9): 1661-7; J. Neuroimmunol., 2000 Nov. 1; 111 (1-2): 224-8; Curr. Opin. Immunol., 1997 December; 9(6): 793-9; JAMA, 1999 September 15; 282 (11) :1076-82; Semin. Cancer Biol., 1996 April; 7 (2): 57-64; J. Interferon Cytokine Res., 2001 April; 21(4): 219-21].
Therefore, it is considered that a compound having PDE 7 inhibiting effect is useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease concerned with T cells.
There has been proposed many compounds selectively inhibit PDE 7. These are for example, imidazopyridine derivatives (International Patent Publication WO 01/34601), dihydropurine derivatives (International Patent Publication WO 00/68203), pyrrole derivatives (International Patent Publication WO 01/32618), benzothiopyranoimidazolone derivatives (DE Patent 19950647), heterocyclic compounds (International Patent Publications WO 02/88080; 02/87513), quinazoline and pyridopyrimidine derivatives (International Patent Publication WO 02/102315), spiro tricyclic compounds (International Patent Publication WO 02/74754), thiazole and oxathiazole derivatives (International Patent Publication WO 02/28847), sulfonamide derivatives (International Patent Publication WO 01/98274), heterobiarylsulfonamide derivatives (International Patent Publication WO 01/74786), dihydroisoquinoline derivatives (International Patent Publication WO 02/40450), guanine derivatives (Bioorg. Med. Chem. Lett., 11(2001), 1081), benzothiadiazine derivatives (J. Med. Chem., 43 (2000), 683) and benzothienothiadiazine derivatives (Eur. J. Med. Chem., 36(2001), 333). However, no curative medicines having PDE 7 inhibiting effect as main pharmacological mechanism have developed up to now.
Though some imidazotriazinone derivatives have been known (For examples: International Patent Publications WO 01/47928; WO 02/98880; WO 02/98879; WO 02/98873; WO 02/79203; WO 02/74774; WO 02/68423; WO 02/64593; WO 02/50078; WO 01/64677; WO 99/67244; WO 99/24433; and EP 1092719), the compounds represented by the general formula of the present application in which R1 is cycloalkyl group or tert-butyl group have never been proposed and there is no suggestions that these compounds have PDE 7 inhibiting effect.
Therefore, the purpose of the present invention is to provide novel compounds having PDE 7 inhibiting effect, and PDE 7 inhibiting composition containing the same as an active ingredient.
The compounds of the present invention inhibit PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compounds of the present invention are useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease. For example, the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia, Crohn's disease, rejection for organ transplantation, GVH disease, and restenosis after angioplasty.